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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Goeritzer, M; Bernhart, E; Plastira, I; Reicher, H; Leopold, C; Eichmann, TO; Rechberger, G; Madreiter-Sokolowski, CT; Prasch, J; Eller, P; Graier, WF; Kratky, D; Malle, E; Sattler, W.
Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro.
Int J Mol Sci. 2020; 21(3):
Doi: 10.3390/ijms21031143
[OPEN ACCESS]
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- Führende Autor*innen der Med Uni Graz
- Göritzer Madeleine
- Sattler Wolfgang
- Co-Autor*innen der Med Uni Graz
- Bernhart Eva Maria
- Eichmann Thomas
- Eller Philipp
- Graier Wolfgang
- Hinteregger Helga
- Kratky Dagmar
- Leopold Christina
- Madreiter-Sokolowski Corina
- Malle Ernst
- Plastira Ioanna
- Prasch Jürgen
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- Abstract:
- During inflammation, activated leukocytes release cytotoxic mediators that compromise blood-brain barrier (BBB) function. Under inflammatory conditions, myeloperoxidase (MPO) is critically involved in inflicting BBB damage. We used genetic and pharmacological approaches to investigate whether MPO induces aberrant lipid homeostasis at the BBB in a murine endotoxemia model. To corroborate findings in a human system we studied the impact of sera from sepsis and non-sepsis patients on brain endothelial cells (hCMEC/D3). In response to endotoxin, the fatty acid, ceramide, and sphingomyelin content of isolated mouse brain capillaries dropped and barrier dysfunction occurred. In mice, genetic deficiency or pharmacological inhibition of MPO abolished these alterations. Studies in metabolic cages revealed increased physical activity and less pronounced sickness behavior of MPO-/- compared to wild-type mice in response to sepsis. In hCMEC/D3 cells, exogenous tumor necrosis factor α (TNFα) potently regulated gene expression of pro-inflammatory cytokines and a set of genes involved in sphingolipid (SL) homeostasis. Notably, treatment of hCMEC/D3 cells with sera from septic patients reduced cellular ceramide concentrations and induced barrier and mitochondrial dysfunction. In summary, our in vivo and in vitro data revealed that inflammatory mediators including MPO, TNFα induce dysfunctional SL homeostasis in brain endothelial cells. Genetic and pharmacological inhibition of MPO attenuated endotoxin-induced alterations in SL homeostasis in vivo, highlighting the potential role of MPO as drug target to treat inflammation-induced brain dysfunction.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Blood-Brain Barrier - metabolism, pathology
- Brain - blood supply, metabolism, pathology
- Capillaries - metabolism, pathology
- Cell Line - administration & dosage
- Cells, Cultured - administration & dosage
- Endothelial Cells - cytology, metabolism, pathology
- Homeostasis - administration & dosage
- Humans - administration & dosage
- Inflammation - metabolism, pathology
- Mice - administration & dosage
- Peroxidase - metabolism
- Sepsis - metabolism, pathology
- Sphingolipids - metabolism
- Find related publications in this database (Keywords)
- blood-brain barrier
- calorimetry
- ceramides
- cytokines
- fatty acid
- mitochondrial function
- myeloperoxidase
- sphingomyelins